Cancer is a devastating disease where available drug therapies often have limited success and are associated with severe toxic side effects. Still, in some cases drug therapy against certain forms of cancer is highly successful, eg. cisplatin treatment against testicular cancer. The success of a given therapy in a given cancer depends upon a web of chemical and biological interactions, where one key factor is the need for targeting of the right molecular target in cancer cells with the most efficient drug(s), showing the least toxic side effects. Many drugs in current use have been employed for decades and there is an urgent need for the identification of new compounds targeting important anticancer molecules. In this project, the researchers wish to search for new compounds that interact with a previously known important drug target for anticancer therapy, the selenium-containing enzyme called thioredoxin reductase 1 (TrxR1). Cellular processes involving selenium and selenoproteins are thought to have a major impact on the development and therapy of cancer and TrxR1 seems to be particularly important in this setting. The enzyme is also known to be targeted by several anticancer agents already used in clinical therapy (eg. cisplatin, chlorambucil, melphalan, nitrosoureas, arsenic trioxide, antitumor quinone compounds and more). Mammalian TrxR1 is a highly reactive selenoprotein, which has major importance for the control of cellular redox systems and antioxidant defense. It is upregulated in many types of cancer and its reactive selenocysteine residue is a presumed direct target for many of the so called electrophilic agents used for anticancer treatment. One of the PI's of this application (Arnir) is an expert in studies of TrxR1 and of its role as an anticancer drug target whereas the other PI (Simeonov) is an expert in conducting high throughput screens (HTS) using libraries of many thousands of well-defined molecules at the NIH Chemical Genomics Center. Joining forces in this project, Arnir and Simeonov have specific aims of identifying novel compounds interacting with TrxR1 and subsequently assessing these as drug leads for new anticancer agents. PUBLIC HEALTH RELEVANCE: Cancer is a devastating disease where available drug therapies often have limited success and are associated with severe toxic side effects. Chemicals targeting the selenium-containing enzyme thioredoxin reductase are likely to serve as promising probes for novel anticancer drugs. Identifying such compounds is the main goal of this research project, which may, for reasons described in detail in the research plan, yield the discovery of compounds having optimal modes of action. This in turn could help improving anticancer efficacy while minimizing toxic side in such treatment.